Transforming growth factor- beta (TGFbeta) is a potent inhibitor of pancreatic cell proliferation. Disruption of the TGFBeta signaling pathway may be important in the development of pancreatic cancer. Recently, deleted in pancreatic carcinoma 4 (DPC4) was identified as a tumor suppressor gene that is inactivatated in 50% of pancreatic tumors. DPC4 (also known as Smad4) act as signaling molecules in TGFBeta-related signaling pathways. Many human pancreatic cancer cell lines are refractory to the growth inhibitory effects of TGF-beta. In this proposal, we will examine the role of Smad genes in TGFBeta- mediated growth regulation in the pancreas and in the development of pancreatic cancer. We have hypothesized that: 1) Smad genes are required for growth inhibition and regulation of differentiation by TGFBeta in pancreatic acinar and duct cells; 2) TGFBeta modulates Smad acitivity by interacting with other signaling pathways, including the MAP kinaase signaling pathway; 3) dominant negative Smads stably transfected into immortalized pancreatic cells will induce tumorigenesis; and 4) functional inactivation of Smad gnes in the pancreas in a transgenic mouse model results in uncontrolled cell proliferation. It is likely that the results of the proposed studies will reveal valuable insight into TGFBeta- mediated growth regulatory mechanism in the pancreas and the role of Smad proteins in neoplastic transformation of the pancreas.